Traumatic brain injury is associated with increased risk of developing neurodegenerative disorders, including Alzheimer?s Disease (AD) and AD-related dementia. This association is complicated owing to differences among individuals in severity of injury, age at time of injury, sex, genetic background, and other variables as well as a lack of understanding of the mechanisms by which mechanical trauma to the brain promotes onset of AD and AD-related dementia many years after the primary injury. Because existing rodent injury models are constrained by limitations of time, expense, and sample size, we developed a Drosophila model to overcome these constraints. In previous work, we demonstrated that the fly model replicates key features of rodent models including Alzheimer?s-like development of behavioral impairment and neurodegeneration. In contrast with rodent models, we can easily study thousands of flies, at low cost over a period of days and weeks rather than months and years. Moreover, with the vast set of genetic, genomic, molecular, and cellular tools and techniques available in Drosophila, we can readily manipulate (or discover) virtually any biochemical pathway that may be relevant to trauma-mediated induction of AD individually or in combination. Furthermore, compared with many other environmental or genetic factors that increase AD risk, we have complete control over trauma in terms of when it is initiated and its severity, enabling us to identify the risk factors that trauma introduces for AD with a precision that is not feasible in other experimental systems. We hypothesize that activation of key regulatory pathways by primary injuries facilitates secondary injuries that over time lead to the characteristic neurodegeneration associated with AD and AD-related dementia. From transcriptomic analysis and other studies, we are focusing on the evolutionarily conserved insulin, mTOR, and innate immune response pathways as well as proteins such as tau and amyloid beta, all of which are also implicated in AD. Using genetic and molecular tools to manipulate these pathways, we will determine how modification of one pathway affects the others and the resultant effects on both short term and long term (i.e. protein aggregation and neurodegeneration) AD-related consequences of trauma. To identify novel genes and pathways associated with trauma-mediated induction of Alzheimer?s-like phenotypes, we will use a collection of hundreds of inbred Drosophila lines with fully sequenced genomes to screen for genetic polymorphisms associated with increased or decreased manifestation of phenotypes such as Alzheimer?s-like neurodegeneration after administration of drugs that modify the pathways under investigation. Together these studies will help elucidate the key molecular and cellular mechanisms by which a primary injury to the brain can trigger secondary injuries that eventually manifest as AD and AD-related dementia. This knowledge should help define new targets for therapeutic intervention for AD and AD-related dementia and lead to better understanding of how other non-trauma risk factors contribute to AD onset.